Neurokinin antagonists for use as medicaments

ABSTRACT

A compound having the general formula (I) and methods of using such compounds for the treatment of diseases and pharmaceutical composition comprising such compounds.

BACKGROUND

[0001] The mammalian neurokinins comprise a class of peptideneurotransmitters which are found in the peripheral and central nervoussystems. The three principal neurokinins are Substance P(SP), NeurokininA (NKA) and Neurokinin B (NKB).

[0002] There are also N-terminally extended forms of at least NKA. Atleast three receptor types are known for the three principalneurokinins. Based upon their relative selectivities favoring theneurokinin agonists SP, NKA and NKB, the receptors are classified asneurokinin 1 (NK₁), neurokinin 2 (NK₂) and neurokinin 3 (NK₃) receptors,respectively.

[0003] It is now recognized that anxiety, stress, and depression areinterrelated conditions (File S E Pharmacol, Biochem & Behavior54/1:3-12, 1996). Moreover, these complex emotional states cannot be duesimply to defects in a single neurotransmitter although 5-HT has beenascribed a principal role (Graeff et al., Pharmacol, Biochem & Behavior54/1: 129-141, 1996). Substance P(SP) was one of the first neuropeptidesto be identified in mammalian brain and it is now accepted that allthree tachykinins are found within the CNS (Iversen L L JPsychopharmacol 3/1: 1-6, 1989), particularly in the striatonigralneurons, hypothalamus and limbic forebrain (ibid). NK₁ and NK₃ receptorshave been identified in the brain as well (Beaujouan et al., Neurosci.18: 857-875, 1986). Controversy has existed regarding the presence ofthe NK₂ receptor in brain, although recent evidence shows receptorlocalization in at least the septal region (Steinberg et al., Eur JNeurosci 10/7:2337-45 1998).

[0004] Pharmacological evidence supporting a role for either NK₁ or NK₂receptors in anxiety disorders has been accumulating from assortedanimal behavioral tests (for examples, see Table 1). Animal models ofdepression, however, have been used rarely to define the potentialutility of NK receptor antagonists. SP stimulates the turnover of otherneurotransmitters involved in depression, i.e., 5-HT in the raphenucleus, an area thought to be linked to depressive phenomena (Forchettiet al., J. Neurochem. 38: 1336-1341, 1982). When injected centrally tonuclei responsible for control of emotion and stress, SP evokes ahemodynamic pressor response bridging this peptide to stress inducedhypertension (Ku et al., Peptides; 1914:677-82, 1998). Moreover, risesin both heart rate and mean arterial blood pressure evoked by physicalstress can be blocked in rodents by centrally administered NK₁ receptorantagonists (Culman et al., J Pharmacol Exp Ther 280/1:238-46, 1997).TABLE 1 Neurokinin receptor antagonist activity in behavioral tests ofanxiety/depression. Cpd (Receptor Author type) Behavioral Test OutcomeTeixeira et al., Eur NK₁ agonists Elevated plus- agonists- J Pharmacol &FK888 maze anxiogenic (NK₁) 5;311(1):7-14, SR48968 antagonists- 1996.(NK₂) anxiolytic File Pharm Bio B CGP 49823 Social anxiolytic58(3):747-752, (NK₁) interaction 1997. Vassout et al CGP 49823 Socialanxiolytic Neuropeptides (NK₁) interaction inactive 26/S1:38, 1994. testElevated antidepressant plus-maze Forced (only at 30 swim test mg/kgbid) (depression model) Stratton et al., Eur. GR100679 Light-dark boxanxiolytic J. Pharmacol. 250: (NK₂) R11-12, 1993. SR48968 (NK₂) Walsh etal., GR159897 Light-dark box anxiolytic Psychopharmacology (NK₂)Marmoset human anxiolytic 121: 186-191, SR48968 intruder 1995. (NK₂)

DESCRIPTION

[0005] This invention relates to internally cyclized naphthamidecompounds; to pharmaceutical compositions containing such compounds; aswell as to their uses and processes for their preparation. Thesecompounds antagonize the pharmacological actions of the neurokinin 1(NK₁) receptor. These compounds are useful whenever such antagonism isdesired. Thus, such compounds are of value in the treatment of thosediseases in which Substance P is implicated, for example, in thetreatment of major depressive disorder, severe anxiety disorders, stressdisorders, major depressive disorder with anxiety, eating disorders,bipolar disorder, substance use disorder, schizophrenic disorders,psychotic disorders, movement disorders, cognitive disorders, depressionand/or anxiety, mania or hypomania, aggressive behaviour, obesity,emesis, rheumatoid arthritis, Alzheimer's disease, cancer, oedema,allergic rhinitis, inflammation, pain, gastrointestinal-hypermotility,Huntington's disease, chronic obstructive pulmonary disorder (COPD),hypertension, migraine, bladder hypermotility, or urticaria.

[0006] Accordingly, the present invention provides the compounds of thegeneral formula Ia:

[0007] The compounds of the present invention may possess a number ofchiral centres, for example at —CH(Ph—X¹,X²)—, and at —CH(R²)—. Thepresent invention covers all isomers, diastereoisomers and mixturesthereof that antagonize NK₁.

[0008] The preferred configuration at —CH(Ph—X¹,X²)— is shown in formula(Ib) hereinbelow:

[0009] X¹ and X² are independently hydrogen or halo, provided that atleast one of X¹ or X² is halo. Favourably, X¹ and X² are both chloro. Ina preferred aspect Ph—X¹,X² is 3,4-dichlorophenyl.

[0010] R^(1a) is H, NR⁹R¹⁰, —OR¹⁰, Cl, Br,

[0011] In another embodiment, R^(1a) is H. NR⁹R¹⁰, —OR⁹,

[0012] R^(1b) and R^(1c) are independently H or —OR⁹, or R^(1b) andR^(1c) together are ═O, ═CH₂ or —OCH₂CH₂O—.

[0013] In one embodiment, R^(1a) is H, NR⁹R¹⁰ or —OR⁹. In anotherembodiment, R^(1a) is

[0014] R^(1b) is H and R^(1c) is H. And in another embodiment, R^(1a) is

[0015] R^(1b) is Hand R^(1c) is H.

[0016] In another embodiment, R^(1a) is H, NR⁹R¹⁰, —OR¹⁰, Cl or Br; andR^(1b) and R^(1c) are independently H or —OR⁹, or R^(1b) and R^(1c)together are ═O, ═CH₂ or —OCH₂CH₂O—.

[0017] In another embodiment, R^(1a) is Cl or Br; and R^(1b) and R^(1c)are both H.

[0018] In another embodiment, R^(1a) is NR⁹R¹⁰, —OR¹⁰; and R^(1b) andR^(1c) are both H or R^(1b) and R^(1c) together are ═O.

[0019] R² is H, oxo, —OR⁹ or —CH₃. In one embodiment, R² is —OR⁵ or—CH₃.

[0020] R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected from H,cyano, nitro, trifluoromethoxy, trifluoromethyl, C₁₋₆alkylsulfonyl,halo, —OR⁹, —OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —NR⁹C(═O)R¹⁰, aminosulfonyl and C₁₋₆alkylsubstituted by any of the hereinabove substituents; wherein at least twoof R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are H. In another embodiment, R⁵, R⁶, R⁷and R⁸ are each H.

[0021] In one embodiment, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are selected from H,cyano, nitro, —S(═O)C₁₋₆alkyl, halo, —OR⁹, —OCH₂O—, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —OC(═O)R⁹,—NR⁹C(═O)R¹⁰, aminosulfonyl and —C₁₋₆alkylcyano; wherein at least threeof R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

[0022] In another embodiment, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are selectedfrom H, cyano, methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo,nitro, cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl,dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyland acetylamino; wherein at least five of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ areH.

[0023] In another embodiment, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are selectedfrom H, cyano, methoxy, ethyl, fluoro and nitro; wherein at least threeof R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are H.

[0024] R⁹ is independently selected from H, C₁₋₆alkyl, C₁₋₄alkoxy, and—OCH₂(CH₂)_(n)phenyl.

[0025] R¹⁰ is independently H or C₁₋₆alkyl, hydroxyC₁₋₆alkyl,(NR⁹R⁹)C₁₋₆alkyl, (NR⁹R⁹)C(═O)C₁₋₆alkyl, —(CH₂)_(o)R¹⁵.

[0026] In another embodiment, R⁹ and R¹⁰ are each independently H orC₁₋₆alkyl;

[0027] R¹¹ is phenyl, substituted in at least the ortho position byC₁₋₆alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl,trifluoromethylthio, trifluoromethylsulfinyl, C₁₋₆alkanesulfonamido,C₁₋₆alkanoyl, C₁₋₆alkoxy-carbonyl, succinamido, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl,C₁₋₆alkoxy-C₁₋₆alkylcarbamoyl, N-methylcarbamoyl, C₁₋₆alkanoylamino,ureido, C₁₋₆ureido, di-C₁₋₆alkylureido, amino, C₁₋₆alkylamino, ordi-C₁₋₆alkylamino.

[0028] R¹² is selected from hydrogen, hydroxy, C₁₋₆alkoxy,C₁₋₆alkanoyloxy, C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino,C₁₋₆alkyl, carbamoyl, C₁₋₆alkylcarbamoyl and bis(C₁₋₆alkyl)carbamoyl.

[0029] R¹³ is —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—.

[0030] R¹⁴ is hydrogen, hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy,C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino, C₁₋₆alkyl,carbamoyl, C₁₋₆alkylcarbamoyl or di-C₁₋₆alkylcarbamoyl.

[0031] R¹⁵ is a 5- or 6-membered saturated or unsaturated heterocyclecontaining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfurand additionally subsituted with 0 or 1 oxo groups; or R¹⁵ is phenylsubstituted by 0, 1, or 2 substitutents selected from halogen,C₁₋₄alkoxy, vicinal-methylenedioxy, —S(═O)_(n)C₁₋₄alkyl, —S(═O)₂NH₂ andC₁₋₄alkyl;

[0032] M is —C(═O)— or —S(═O)₂—.

[0033] L is —NH— or —CH₂—.

[0034] Y and Z are independently selected from CH₂, O, S, S═O andS(═O)₂, wherein at least one of Y and Z is CH₂. In another embodiment, Yand Z are CH₂ or O, wherein Y does not equal Z.

[0035] n is independently, at each instance, 0 or 1;

[0036] o is independently, at each instance, 1, 2 or 3.

[0037] Another aspect of the invention involves a pharmaceuticalcomposition comprising a therapeutically effective amound of a compoundof formula Ia.

[0038] Another aspect of the invention involves a method of treatingmajor depressive disorder, severe anxiety disorders, stress disorders,major depressive disorder with anxiety, eating disorders, bipolardisorder, general and specific craving, substance use disorder,schizophrenic disorders, psychotic disorders, movement disorders,cognitive disorders, depression and/or anxiety, mania or hypomania,aggressive behaviour, obesity, emesis, rheumatoid arthritis, Alzheimer'sdisease, cancer, oedema, allergic rhinitis, inflammation, pain,gastrointestinal-hypermotility, Huntington's disease, COPD,hypertension, migraine, bladder hypermotility, or urticaria comprisingadministering an effective amount of an NK1 antagonist of formula Ia.

[0039] Particular compounds of this invention are provided as theExamples hereinbelow.

[0040] C_(Y-Z)alkyl, unless otherwise specified, means an alkyl chaincontaining a minimum Y total carbon atoms and a maximum Z total carbonatoms. These alkyl chains may be branched or unbranched, cyclic, acyclicor a combination of cyclic and acyclic. For example, the followingsubstituents would be included in the general description “C₄₋₇alkyl”:

[0041] Pharmaceutically-acceptable salts may be prepared from thecorresponding acid in conventional manner.Non-pharmaceutically-acceptable salts may be useful as intermediates andas such are another aspect of the present invention.

[0042] The symbol “═O” means a double bonded oxygen, and when thissymbol is used attached to a carbon it forms a carbonyl group.

[0043] Some of the compounds of the present invention are capable offorming salts with various inorganic and organic acids and bases andsuch salts are also within the scope of this invention. Examples of suchacid addition salts include acetate, adipate, ascorbate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,citrate, cyclohexyl sulfamate, ethanesulfonate, fumarate, glutamate,glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate,malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate,oxalate, pamoate, persulfate, phenylacetate, phosphate, picrate,pivalate, propionate, quinate, salicylate, stearate, succinate,sulfamate, sulfanilate, sulfate, tartrate, tosylate(p-toluenesulfonate), and undecanoate. Base salts include ammoniumsalts, alkali metal salts such as sodium, lithium and potassium salts,alkaline earth metal salts such as aluminum, calcium and magnesiumsalts, salts with organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine, ornithine, and so forth. Also, basic nitrogen-containing groupsmay be quaternized with such agents as: lower alkyl halides, such asmethyl, ethyl, propyl, and butyl halides; dialkyl sulfates likedimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such asdecyl, lauryl, myristyl and stearyl halides; aralkyl halides like benzylbromide and others. Non-toxic physiologically-acceptable salts arepreferred, although other salts are also useful, such as in isolating orpurifying the product.

[0044] The salts may be formed by conventional means, such as byreacting the free base form of the product with one or more equivalentsof the appropriate acid in a solvent or medium in which the salt isinsoluble, or in a solvent such as water, which is removed in vacuo orby freeze drying or by exchanging the anions of an existing salt foranother anion on a suitable ion-exchange resin.

[0045] In order to use a compound of the formula (I) or apharmaceutically acceptable salt thereof for the therapeutic treatment(including prophylactic treatment) of mammals including humans, it isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition.

[0046] Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)or a pharmaceutically acceptable salt and pharmaceutically acceptablecarrier.

[0047] The pharmaceutical compositions of this invention may beadministered in standard manner for the disease condition that it isdesired to treat, for example by oral, topical, parenteral, buccal,nasal, vaginal or rectal administration or by inhalation orinsufflation. For these purposes the compounds of this invention may beformulated by means known in the art into the form of, for example,tablets, capsules, aqueous or oily solutions, suspensions, emulsions,creams, ointments, gels, nasal sprays, suppositories, finely dividedpowders or aerosols or nebulisers for inhalation, and for parenteral use(including intravenous, intramuscular or infusion) sterile aqueous oroily solutions or suspensions or sterile emulsions.

[0048] In addition to the compounds of the present invention thepharmaceutical composition of this invention may also contain, or beco-administered (simultaneously or sequentially) with, one or morepharmacological agents of value in treating one or more diseaseconditions referred to herein.

[0049] The pharmaceutical compositions of this invention will normallybe administered to humans so that, for example, a daily dose of 0.01 to25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) isreceived. This daily dose may be given in divided doses as necessary,the precise amount of the compound received and the route ofadministration depending on the weight, age and sex of the patient beingtreated and on the particular disease condition being treated accordingto principles known in the art.

[0050] Typically unit dosage forms will contain about 1 mg to 500 mg ofa compound of this invention. For example a tablet or capsule for oraladministration may conveniently contain up to 250 mg (and typically 5 to100 mg) of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof. In another example, for administration byinhalation, a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof may be administered in a daily dosage range of 5to 100 mg, in a single dose or divided into two to four daily doses. Ina further example, for administration by intravenous or intramuscularinjection or infusion, a sterile solution or suspension containing up to10% w/w (and typically 5% w/w) of a compound of the formula (I) or apharmaceutically acceptable salt thereof may be used.

[0051] Therefore in a further aspect, the present invention provides acompound of the formula (I) or a pharmaceutically acceptable saltthereof for use in a method of therapeutic treatment of the human oranimal body.

[0052] In yet a further aspect the present invention provides a methodof treating a disease condition wherein antagonism of the NK₁ receptoris beneficial which comprises administering to a warm-blooded animal aneffective amount of a compound of the formula (I) or apharmaceutically-acceptable salt thereof. The present invention alsoprovides the use of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof in the preparation of a medicament for use in adisease condition wherein antagonism of the NK₁ receptor is beneficial.

[0053] The compounds of the formula (I) and their pharmaceuticallyacceptable salts may be made by processes as described and exemplifiedherein and by processes similar thereto and by processes known in thechemical art. If not commercially available, starting materials forthese processes may be made by procedures which are selected from thechemical art using techniques which are similar or analogous to thesynthesis of known compounds.

[0054] It is well known in the art how to prepare optically-active forms(for example, by resolution of the racemic form or by synthesis fromoptically-active starting materials) and how to determine the NK₁antagonist properties by the standard tests known in the art and thosedescribed hereinafter.

[0055] Some individual compounds within the scope of this invention maycontain double bonds. Representations of double bonds in this inventionare meant to include both the E and the Z isomer of the double bond.Additionally, some species within the scope of this invention maycontain one or more asymmetric centers. This invention includes the useof any of the optically pure stereoisomers as well as any combination ofstereoisomers.

[0056] In general, the macrocyclic naphthamides can exist as a mixtureof conformational isomers (atropisomers) (“The Chemistry of RotationalIsomers”; Oki, M.; Springer Verlag, NY; 1993). Where individualatropisomers have been isolatable, distinct chemical and biologicalproperties have been observed. The compounds of this invention compriseboth mixtures of, and individual, atropisomers.

[0057] The following biological test methods, data and Examples serve toillustrate and further describe the invention.

[0058] The utility of a compound of the invention or a pharmaceuticallyacceptable salt thereof (hereinafter, collectively referred to as a“compound”) may be demonstrated by standard tests and clinical studies,including those disclosed in the publications described below.

[0059] SP Receptor Binding Assay (Test A)

[0060] The ability of a compound of the invention to antagonize thebinding of SP at the NK₁ receptor may be demonstrated using an assayusing the human NK₁ receptor expressed in Mouse Erythroleukemia (MEL)cells. The human NK₁ receptor was isolated and characterized asdescribed in: B. Hopkins, et al. “Isolation and characterization of thehuman lung NK₁ receptor cDNA” Biochem. Biophys. Res. Comm., 1991, 180,1110-1117; and the NK₁ receptor was expressed in Mouse Erythroleukemia(MEL) cells using a procedure similar to that described in Test B below.

[0061] Neurokinin A (NKA) Receptor Binding Assay (Test B)

[0062] The ability of a compound of the invention to antagonize thebinding of NKA at the NK₂ receptor may be demonstrated using an assayusing the human NK₂ receptor expressed in Mouse Erythroleukemia (MEL)cells, as described in: Aharony, D., et al. “Isolation andPharmacological Characterization of a Hampster Neurokinin A ReceptorcDNA” Molecular Pharmacology, 1994, 45, 9-19.

[0063] The selectivity of a compound for binding at the NK₁ and the NK₂receptors may be shown by determining its binding at other receptorsusing standard assays, for example, one using a tritiated derivative ofNKB in a tissue preparation selective for NK₃ receptors. In general, thecompounds of the invention which were tested demonstrated statisticallysignificant binding activity in Test A and Test B with a K_(i) of 1 mMor much less typically being measured.

[0064] Rabbit Pulmonary Artery: NK₁ in vitro Functional Assay (Test C)

[0065] The ability of a compound of the invention to antagonize theaction of the agonist Ac-[Arg⁶, Sar⁹, Met(O₂)¹¹] Substance P (6-11),ASMSP, in a pulmonary tissue may be demonstrated as follows.

[0066] Male New Zealand white rabbits are euthanized via i.v. injectioninto the ear vein with 60 mg/kg Nembutal (50 mg/mL). Preceding theNembutal into the vein is Heparin (1000 units/mL) at 0.0025 mL/kg foranticoagulant purposes. The chest cavity is opened from the top of therib cage to the sternum and the heart, lungs and part of the trachea areremoved. The pulmonary arteries are isolated from the rest of thetissues and cut in half to serve as pairs.

[0067] The segments are suspended between stainless steel stirrups, soas not to remove any of the endothelium, and placed in water-jacketed(37.0° C.) tissue baths containing physiological salt solution of thefollowing composition (mM): NaCl, 118.0; KCl, 4.7; CaCl₂, 1.8; MgCl₂,0.54; NaH₂PO₄, 1.0; NaHCO₃, 25.0; glucose, 11.0; indomethacin, 0.005 (toinhibit cyclooxygenase); and dl-Propranolol, 0.001 (to block βreceptors); gassed continuously with 95% O₂-5% CO₂. Responses aremeasured on a Grass polygraph via Grass FT-03 transducers.

[0068] Initial tension placed on each tissue is 2 grams, which ismaintained throughout the 1.0 hour equilibration period. Tissues arewashed with the physiological salt solution at 15 minute intervals. Atthe 30 and 45 minute wash the following treatments are added: 1×10⁻⁶ MThiorphan (to block E.C.3.4.24.11), 3×10⁻⁸M(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide(to block NK₂ receptors), and the given concentration of the compoundbeing tested. At the end of the 1.0 h equilibration, 3×10⁻⁶Mphenylephrine hydrochloride is added for 1.0 h. At the end of 1.0 h, adose relaxation curve to ASMSP is done. Each tissue is treated as aindividual and is considered finished when it fails to relax further for2 consecutive doses. When a tissue is complete, 1×10⁻³ M Papaverine isadded for maximum relaxation.

[0069] Percent inhibition is determined when a tested compound producesa statistically significant (p<0.05) reduction of the total relaxationwhich is calculated using the total relaxation of the Papaverine as100%. Potencies of the compounds are determined by calculating theapparent dissociation constants (K_(B)) for each concentration testedusing the standard equation:

KB=[antagonist]/(dose ratio−1)

[0070] where dose ratio=antilog[(agonist−log molar EC₅₀ withoutcompound)−(−log molar EC₅₀ with compound)]. The K_(B) values may beconverted to the negative logarithms and expressed as −log molar K_(B)(i.e. pK_(B)). For this evaluation, complete concentration-responsecurves for agonist obtained in the absence and presence of the compoundtested using paired pulmonary artery rings. The potency of the agonistis determined at 50% of its own maximum relaxation in each curve. TheEC₅₀ values are converted to negative logarithms and expressed as −logmolar EC₅₀.

[0071] NK₂ in vitro Functional Assay (Test D)

[0072] The ability of a compound of the invention to antagonize theaction of the agonist [β-ala8] NKA (4-10), BANK, in a pulmonary tissuemay be demonstrated as follows. Male New Zealand white rabbits areeuthanized via i.v. injection into the ear vein with 60 mg/kg Nembutal(50 mg/mL). Preceding the Nembutal into the vein is Heparin (1000units/mL) at 0.0025 mL/kg for anticoagulant purposes. The chest cavityis opened from the top of the rib cage to the sternum and a smallincision is made into the heart so that the left and right pulmonaryarteries can be cannulated with polyethylene tubing (PE260 and PE190respectively). The pulmonary arteries are isolated from the rest of thetissues, then rubbed over an intimal surface to remove the endothelium,and cut in half to serve as pairs. The segments are suspended betweenstainless steel stirrups and placed in water-jacketed (37.0° C.) tissuebaths containing physiological salt solution of the followingcomposition (mM): NaCl, 118.0; KCl, 4.7; CaCl₂, 1.8; MgCl₂, 0.54;NaH₂PO₄, 1.0; NaHCO₃, 25.0; glucose, 11.0; and indomethacin, 0.005 (toinhibit cyclooxygenase); gassed continuously with 95% O₂-5% CO₂.Responses are measured on a Grass polygraph via Grass FT-03 transducers.

[0073] Initial tension placed on each tissue is 2 g, which is maintainedthroughout the 45 min equilibration period. Tissues are washed with thephysiological salt solution at 15 min intervals. After the 45 minequilibration period, 3×10⁻² M KCl is given for 60 min to test theviability of the tissues. The tissues are then washed extensively for 30min. The concentration of the compound being tested is then added for 30min. At the end of the 30 min, a cumulative dose response curve to BANKis performed. Each tissue is treated as a individual and is consideredfinished when it fails to contract further for 2 consecutive doses. Whena tissue is complete, 3×10⁻²M BaCl₂ is added for maximum contraction.

[0074] Percent inhibition is determined when a tested compound producesa statistically significant (p<0.05) reduction of the total contractionwhich is calculated using the total contraction of the BaCl₂ as 100%.Potencies of the compounds are determined by calculating the apparentdissociation constants (KB) for each concentration tested using thestandard equation:

K _(B)=[antagonist]/(dose ratio−1)

[0075] where dose ratio=antilog[(agonist−log molar EC₅₀ withoutcompound)−(−log molar EC₅₀ with compound)]. The K_(B) values may beconverted to the negative logarithms and expressed as −log molar K_(B)(i.e. pK_(B)). For this evaluation, complete concentration-responsecurves for agonist obtained in the absence and presence of the compoundtested using paired pulmonary artery rings. The potency of the agonistis determined at 50% of its own maximum relaxation in each curve. TheEC₅₀ values are converted to negative logarithms and expressed as −logmolar EC₅₀.

[0076] NK₁ and NK₂ in vivo Functional Assay (Test E)

[0077] The activity of a compound as an antagonist of NK₁ and/or NK₂receptors also may be demonstrated in vivo in laboratory animals asdescribed in: Buckner et al. “Differential Blockade by Tachykinin NK₁and NK₂ Receptor Antagonists of Bronchoconstriction Induced byDirect-Acting Agonists and the Indirect-Acting Mimetics Capsaicin,Serotonin and 2-Methyl-Serotonin in the Anesthetized Guinea Pig.” J.Pharm. Exp. Ther., 1993, Vol 267(3), pp.1168-1175. The assay is carriedout as follows.

[0078] Compounds are tested in anesthetized guinea pigs pretreated withi.v. indomethacin (10 mg/kg, 20 min), propranolol (0.5 mg/kg, 15 min),and thiorphan (10 mg/kg, 10 min).

[0079] Antagonists or vehicle are administered i.v. and orally, 30 and120 min prior to increasing concentrations of agonist, respectively. Theagonists used in these studies are ASMSP(Ac-[Arg⁶,Sar⁹,Met(O₂)¹¹]-SP(6-11)) and BANK (β-ala-8 NKA4-10).

[0080] Administered i.v., ASMSP is selective for NK₁ receptors, and BANKis selective for NK₂ receptors. Maximum response is defined as zeroconductance (G_(L), 1/Rp). ED₅₀ values are calculated (the dose ofagonist resulting in a reduction of G_(L) to 50% of baseline), andconverted to the negative logarithm (−log ED₅₀). The ED₅₀ values,obtained in the presence (P) and absence (A) of antagonist, are used tocalculate a Dose Ratio (P/A), an expression of potency. Data areexpressed as mean±SEM and statistical differences were determined usingANOVA/Tukey-Kramer and Student's t-test, with p<0.05 consideredstatistically significant.

[0081] Compounds of the present invention exhibit marked activity in theforegoing tests and are considered useful for the treatment of thosediseases in which the NK₁ and/or NK₂ receptor is implicated, forexample, in the treatment of asthma and related conditions.

EXAMPLES

[0082] The invention will now be illustrated by the followingnon-limiting examples, in which, unless stated otherwise:

[0083] (i) temperatures are given in degrees Celsius (° C.); unlessotherwise stated, operations were carried out at room or ambienttemperature, that is, at a temperature in the range of 18-25° C.;

[0084] (ii) organic solutions were dried over anhydrous sodium sulfate;evaporation of solvent was carried out using a rotary evaporator underreduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bathtemperature of up to 60° C.;

[0085] (iii) chromatography means flash chromatography on silica gel;thin layer chromatography (TLC) was carried out on silica gel plates;

[0086] (iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

[0087] (v) melting points are uncorrected and (dec) indicatesdecomposition;

[0088] (vi) final products had satisfactory proton nuclear magneticresonance (NMR) spectra;

[0089] (vii) when given, NMR data is in the form of delta values formajor diagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at 300 MHzusing deuterated chloroform (CDCl₃) as solvent; conventionalabbreviations for signal shape are used; for AB spectra the directlyobserved shifts are reported; coupling constants (J) are given in Hz; Ardesignates an aromatic proton when such an assignment is made;

[0090] (viii) reduced pressures are given as absolute pressures inpascals (Pa); elevated pressures are given as gauge pressures in bars;

[0091] (ix) solvent ratios are given in volume:volume (v/v) terms; and

[0092] (x) Mass spectra (MS) were run using an automated system withatmospheric pressure chemical ionization (APCI). Generally, only spectrawhere parent masses are observed are reported. The lowest mass major ionis reported for molecules where isotope splitting results in multiplemass spectral peaks (for example when chlorine is present).

[0093] Terms and abbreviations: solvent mixture compositions are givenas volume percentages or volume ratios. In cases where the NMR spectraare complex, only diagnostic signals are reported. AcOH=acetic acid,atm=atmospheric pressure, Boc=t-butoxycarbonyl, Cbz=benzyloxycarbonyl,DCM=methylene chloride, DIPEA=diisopropylethylamine,DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide, Et₂O=diethyl ether,EtOAc=ethyl acetate, equiv.=equivalent(s), h=hour(s), HPLC=highperformance liquid chromatography, MeOH=methanol, min=minutes,NMR=nuclear magnetic resonance, RT=room temperature, psi=pounds persquare inch, TFA=trifluoroacetic acid, THF=tetrahydrofuran.

[0094] Where noted that a compound was converted to the citrate salt,the free base was combined with citric acid (1.0 equivalents) inmethanol, concentrated under reduced pressure and dried under vacuum(25-70° C.).

Example 1

[0095]

[0096] To a stirred solution of4-[(S)-2-methylsulfinylphenyl]-piperidine (0.078 g, 0.326 mmol) and MeOH(8 mL) was added AcOH (0.02 mL, 0.359 mmol), a solution of 1i (0.148 g,0.326 mmol) in MeOH (6 mL). The mixture was stirred at RT for 30 min anda solution of sodium cyanoborohydride (0.023 g, 0.359 mmol) in MeOH (2mL) was added and stirring continued at RT overnight. The mixture wasquenched with saturated NaHCO₃ and partitioned between DCM and water.The organic phase was collected, consecutively washed with saturatedaqueous NaHCO₃ and water, dried (Na₂SO₄), filtered and the solventremoved in vacuo. The crude product was purified by gradientchromatography (2%, 5% MeOH/DCM) to yield 1 (0.194 g, 90%) as a whitesolid which was converted to the citrate salt. ¹H NMR (300 MHz, CDCl₃) δ8.25 (s, 1H), 8.0 (m, 2H), 7.84 (d, 1H), 7.66 (t, 1H), 7.56 (t, 1H),7.48-7.35 (m, 5H), 7.17 (dd, 1H), 4.43-4.30 (m, 2H), 4.4 (m, 1H), 3.84(m, 1H), 3.30 (m, 2H), 3.18 (m, 1H), 3.04-2.91 (m, 2H), 2.72 (m, 1H),2.68 (s, 3H), 2.27 (m, 2H), 2.07-1.61 (m, 8H). MS APCI, m/z=660 (M⁺).Analysis for C₃₆H₃₅N₃O₃SCl₂.1.0C₆H₈O₇.2.0H₂O. Calculated: C, 56.75; H,5.33; N, 4.72. Found: C, 56.50; H, 5.26; N, 4.43.

[0097] The requisite 1i was prepared as follows.

[0098] 1a

[0099] To a stirred solution of 3-cyano-2-methoxy-1-naphthoic acid(0.506 g, 2.22 mmol) and DCM (28 mL) was added oxalyl chloride (0.24 mL,2.78 mmol) and 2 drops of DMF. After 2 h at RT toluene (10 mL) was addedand the solvent removed in vacuo and the residue set under vacuum pumppressure for 2 h. The crude 3-cyano-2-methoxy-1-naphthalenecarbonylchloride (1a) was used without purification.

[0100] 1b

[0101] A stirred solution of(S)-2-(3,4-dichlorophenyl)-4-hydroxybutylamine (0.518 g, 2.22 mmol) inDCM (20 mL) was treated with 10% NaOH (2.67 mL) and cooled to 0° C. Asolution of la (2.22 mmol) in DCM (10 mL) was added and the stirredreaction allowed to warm in the ice bath to RT overnight. The reactionwas partitioned between additional DCM and water, the organic phaseseparated, washed with water, dried (Na₂SO₄) and the solvent removed invacuo. The crude material was purified by gradient chromatography (0.5%,2.0%, 5.0% MeOH/DCM) to give 1b (0.95 g, 97%) as a white solid. ¹H NMR(300 MHz, CDCl₃) δ 8.16 (s, 1H), 7.82 (d, 1H), 7.65-7.32 (m, 5H), 7.14(dd, 1H), 6.18 (t, 1H), 3.98 (s, 3H), 3.8-3.68 (m, 3H), 3.54 (m, 1H)3.18 (m, 1H), 2.05 (m, 1H), 1.77 (m, 1H), MS APCI, m/z=443 (M⁺).

[0102] 1c

[0103] To a stirred solution of 1b (5.51 g, 12.46 mmol) and DCM (100 mL)was successively added tert-butyldimethylsilylchloride (2.82 g, 18.69mmol), 4-dimethylaminopyridine (0.076 g, 0.623 mmol), and triethylamine(2.78 mL, 19.94 mmol) and the reaction mixture stirred at RT overnight.The mixture was partitioned between additional DCM and water, theorganic layer was collected, washed with water and dried (Na₂SO₄). Thecrude product was purified by gradient chromatography (eluting with 70%,50% hexane/Et₂O) to yield 1c (6.48 g, 94%) as a white solid. ¹H NMR (300MHz, CDCl₃) δ8.2 (s, 1H), 7.82 (d, 1H), 7.62-7.36 (m, 51), 7.16 (dd,1H), 6.14 (t, 1H), 4.01 (s, 3H), 3.88-3.78 (m, 2H), 3.64 (m, 1H), 3.47(m, 1H), 3.20 (m, 1H), 2.03 (m, 1H), 1.84 (m, 1H), 0.86 (s, 9H), 0.016(s, 6H). MS APCI, m/z=557 (M⁺).

[0104] 1d

[0105] A 3-neck flask containing a magnetic stirrer and magnesium chips(0.68 g, 27.96 mmol) was flamed dried and allowed to cool to RT undernitrogen. After the addition of Et₂O (30 mL), benzene (15 mL) and iodine(3.55 g, 13.98 mmol), the reaction mixture was heated at reflux for 2 h.After cooling to RT the solution was transferred by cannula to a flaskcontaining 1c (6.48 g, 11.65 mmol) in 108 mL benzene. Heating underreflux was continued for 1 h, the mixture allowed to cool to RT then 1NHCl and DCM were introduced and the mixture stirred for 15 min. Thecollected organic phase was washed twice with water, dried (Na₂SO₄)filtered and concentrated. The crude product was purified by gradientchromatography (eluting with 2%, 5%, 10% MeOH/DCM) to give 1d (5.57 g,88%) as a light yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 11.91 (bs, 1H),8.15 (s, 1H), 7.77 (m, 1H), 7.45-7.13 (m, 6H), 6.28 (m, 1H), 3.96 (m,1H), 3.62-3.25 (m, 4H), 1.99 (m, 1H), 1.84 (m, 1H), 0.70 (s, 9H), 0.011(s, 6H). MS APCI, m/z=543 (M⁺).

[0106] 1e

[0107] A stirred mixture of 1d (1.50 g, 2.77 mmol), DMF (12.0 mL), K₂CO₃(0.574 g, 4.15 mmol) and 2-chloro-ethanol (0.21 mL, 3.11 mmol) washeated at 88° C. for 72 h. and then quenched with aqueous NH₄Cl. Themixture was partitioned between DCM and water, the organic layercollected, washed twice with water, dried (Na₂SO₄), filtered andconcentrated. The crude orange solid (1.30 g), consisted of product andstarting material in a 1:3 ratio (by NMR) and was used in the next stepwithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 8.22 (s) 1e, δ8.20 (s) 1d. MS APCI, m/z=587 (M⁺) 1e.

[0108] 1f

[0109] To a stirred solution of the above 1e/1d mixture (1.30 g) and DCM(20 mL) was added triethylamine (0.47 mL, 2.48 mmol), the mixture cooledto 0° C., and methanesulfonyl chloride (0.19 mL, 2.48 mmol) was added.The mixture partitioned between additional DCM and water, the organicphase collected, washed twice with 1N HCl, twice with saturated aqueousNaHCO₃ and dried over Na₂SO₄. Purification by gradient chromatography(40%, 20% hexane/Et₂O) gave if (0.24 g, 13% from 1d) as a white solid.¹H NMR (300 MHz, CDCl₃) δ 8.24 (s, 1H), 7.86 (dd, 11), 7.58 (m, 2H),7.47-7.30 (m, 3H), 7.18 (dd, 1H), 6.21 (t, 1H), 4.56 (m, 2H), 4.49 (m,2H), 3.94-3.81-(m, 2H), 3.66 (m, 1H), 3.48 (m, 1H), 3.21 (m, 1H), 3.16(s, 3H), 2.03 (m, 1H), 1.85 (m, 1H), 0.86 (s, 9H), 0.026 (s, 6H). MSAPCI, m/z=665 (M⁺).

[0110] 1g

[0111] To a stirred solution of 1f (0.24 g, 0.36 mmol) and THF (12.0 mL)was added 95% NaH (0.010 g, 0.38 mmol) and the mixture refluxed for 40min. After quenching with NH₄Cl, the mixture was partitioned between DCMand water, the organic phase was collected, washed twice with water,dried (Na₂SO₄), filtered and concentrated. Purification by gradientchromatography (80%, 60%, 20% hexane/Et₂O) gave 1g (0.23 g, 71%) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 8.25 (s, 1H), 7.91-7.82 (m, 2H),7.64 (t, 1H), 7.54 (t, 1H), 7.39 (m, 2H), 7.16 (dd, 1H), 4.43 (m, 2H),3.96 (m, 2H), 3.64 (m, 1H), 3.46-3.27 (m, 4H), 2.04 (m, 1H), 1.87 (m,1H), 0.89 (s, 9H), 0.011 (s, 6H). MS APCI, m/z=569 (M⁺).

[0112] 1h

[0113] A solution of 1g (0.23 g, 0.397 mmol) in CH₃CN (5 mL) was addedto stirred 5% HF/CH₃CN (4 mL 50% HF/36 mL CH₃CN) and the mixture stirredat RT for 40 min. The reaction was quenched by the addition of DCM,water and solid NaHCO₃ until pH˜6-7 was obtained. The organic phase wascollected, washed twice with water, dried (Na₂SO₄), filtered andconcentrated to yield 1h (0.175 g, 97%) as a white solid. ¹H NMR (300MHZ, CDCl₃) δ 8.25 (s, 1H), 7.97 (d, 1H), 7.84 (d, 1H), 7.65 (t, 1H),7.54 (t, 1H), 7.41 (m, 2H), 7.17 (dd, 1H), 4.39 (m, 2H), 4.07 (m, 1H),3.89-3.69 (m, 2H), 3.55 (m, 1H), 3.37-3.29 (m, 3H), 2.11-1.91 (m, 2H),1.74 (t, 1H). MS APCI m/z=455 (M⁺).

[0114] 1i

[0115] To a stirred −78° C. solution of oxalyl chloride (0.05 mL, 0.58mmol) and DCM (8 mL) was added a solution of DMSO (0.08 mL, 1.16 mmol)in DCM (4 mL). After stirring for 5 min a solution of 1h (0.175 g, 0.385mmol) in DCM (6 mL) was added. After stirring for 15 min, triethylamine(0.32 mL, 2.31 mmol) was added. The mixture was stirred an addition 15min in the bath, the bath removed and stirring continued at ambienttemperature for an additional 2 h. The reaction mixture was partitionedbetween DCM and a large volume of water, the organic phase collected,washed with an additional large volume of water, the organic phase dried(Na₂SO₄), filtered and concentrated. Gradient chromatography (1%, 20%,50% Et₂O/DCM) yielded 0.148 g, (84%) of white solid 1i. ¹H NMR (300 MHz,CDCl₃) δ 9.80 (s, 1H), 8.26 (s, 1H), 7.93-7.83 (m, 2H), 7.64 (t, 1H),7.54 (t, 1H), 7.43 (m, 2H), 7.18 (dd, 1H), 4.42 (m, 2H), 3.95 (m, 2H),3.75-3.75 (m, 1H), 3.40 (m, 2H), 3.10-2.90 (m, 2H). MS APCI, m/z=453(M⁺).

Example 2

[0116]

[0117] 4-[(S)-2-methylsulfinyl-phenyl]-piperidine (0.134 g, 0.560 mmol)was reacted with 2i (0.261 g, 0.560 mmol) in the presence of sodiumcyanoborohydride under the standard reductive amination conditionsdescribed in the preparation of 1. The crude product was purified bygradient chromatography (2%, 5% MeOH/DCM) to yield 2 (0.271 g, 72%) as awhite solid which was converted to the citrate salt. ¹H NMR (300 MHz,CDCl₃) δ 8.20-8.14 (m, 1H), 7.98 (m, 1H), 7.81-7.70 (m, 1H), 7.53-7.33(m, 7H), 7.25 (m, 1H), 6.72 (m, 1H), 4.83-4.58 (m, 2H), 4.17 (m, 1H),3.60-3.32 (m, 2H), 3.14-2.91 (m, 3H), 2.79 (m, 1H), 2.68 (s, 3H),2.33-2.26 (m, 2H), 2.19-1.63 (m, 11H). MS APCI, m/z=674. Analysis forC₃₇H₃₇N₃O₃SCl₂.1.0C₆H₈O₇.1.8H₂O. Calculated: C, 57.43; H, 5.44; N, 4.67.Found: C, 57.43; H, 5.36; N, 4.49.

[0118] The requisite 2i was prepared as follows.

[0119] 2e

[0120] A stirred mixture of 1d (4.24 g, 7.82 mmol), 3-chloropropanol(0.74 mL, 8.80 mmol), DMF (40.0 mL) and K₂CO₃ (1.621 g, 11.73 mmol) washeated at 88° C. for 48 h. The reaction was worked up as described forle yielding material that had a 2e:1d ratio of 1:2 (¹H NMR). Thismaterial was resubjected to the same reaction conditions described abovereturning material with a 2e:1d ratio of 42:58 (¹H NMR). This materialwas used in the next step without purification. ¹H NMR (300 MHz, CDCl₃)ratio determined by integration comparison of the amide proton of 1d atδ6.31 (t) and the amide proton of 2e at δ6.20 (t). MS APCI, m/z=601 (M⁺)for 2e m/z=543 (M⁺) for 1d.

[0121] 2f

[0122] The above 2e:1d mixture (4.11 g) was reacted with methanesulfonylchloride (0.64 mL, 8.19 mmol) as described for 1f. Purification bygradient chromatography (40%, 20% hexane/Et₂O) returned 2f (0.89 g, 17%based on 1d) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.19 (s, 1H),7.82 (m, 1H), 7.54 (m, 2H), 7.46-7.37 (m, 3H), 7.16 (dd, 1H), 6.10 (t,1H), 4.50 (t, 2H), 4.33-4.25 (m, 2H), 3.90-3.80 (m, 2H), 3.64 (m, 1H),3.44 (m, 1H), 3.14 (m, 1H), 3.08 (s, 3H), 2.27-2.20 (m, 2H), 1.99 (m,1H), 1.79 (m, 1H), 0.83 (s, 9H), −0.025 (s, 6H). MS APCI, m/z=679 (M⁺).

[0123] 2g

[0124] Using the procedure described in the preparation of 1g, 2f (0.890g, 1.31 mmol) in THF (36.0 mL) was reacted with 90% NaH (0.035 g, 1.39mmol). Purification by gradient chromatography (80%, 60% hexane/Et₂O)gave 2g (0.411 g, 54%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.19-8.12 (m, 1H), 7.70 (m, 1H), 7.54-7.34 (m, 4H), 7.24 (m, 1H), 6.64(m, 1H), 4.88-4.59 (m, 2H), 4.19 (m, 1H), 3.62 (m, 1H), 3.49-3.07 (m,5H), 2.20-1.83 (m, 4H), 0.88 (s, 9H), 0.11 (s, 6H). MS APCI, m/z=583(M⁺).

[0125] 2h

[0126] Using the desilylation conditions described in the preparation of1h, 2g (0.411 g, 0.706 mmol) was reacted with 5% HF/CH₃CN (7 mL 50%HF/63 mL CH₃CN) to yield 2h (0.316 g, 95%) as a white solid. Nopurification was required. ¹H NMR (300 MHz, CDCl₃) δ 8.21-8.10 (m, 1H),8.01-7.34 (m, 5H), 7.25 (m, 1H), 6.65 (m, 1H), 4.83-4.58 (m, 2H),4.20-4.13 (m, 1H), 3.69 (m, 1H), 3.50-2.72 (m, 5H), 2.17-1.80 (m, 4H),1.45 (m, 1H). MS APCI, m/z=469 (M⁺).

[0127] 2i

[0128] Using the standard Swern oxidizing conditions described in thepreparation of 1i, 2h (0.271 g, 0.580 mmol) was converted to, followinggradient chromatography (1%, 20%, 50% Et₂O/DCM), 0.261 g (96%) of 2i asa white solid. ¹H NMR (300 MHz, CDCl₃) δ 9.79 (m, 1H), 8.28-8.25 (m,1H), 7.98-7.37 (m, 5H), 7.25 (m, 1H), 6.68 (m, 1H), 4.82-4.57 (m, 2H),4.22-4.15 (m, 1H), 3.92-3.36 (m, 3H), 3.17-2.88 (m, 3H), 2.19-1.97 (m,2H). MS APCI, m/z=467 (M⁺).

Example 3

[0129]

[0130] 4-[(S)-2-Methylsulfinyl-phenyl]-piperidine (0.089 g, 0.374 mmol)was reacted with 3i (0.18 g, 0.374 mmol) in the presence of sodiumcyanoborohydride under the standard reductive amination conditionsdescribed for 1i. The crude product was purified by gradientchromatography (eluting with 2%, 3%, 5% MeOH/DCM) to give 3 (0.197 g,77%) as a white solid which was converted to the citrate salt. ¹H NMR(300 MHz, CDCl₃) δ8.15 (s, 1H), 7.98 (m, 1H), 7.74 (m, 1H), 7.49-7.43(m, 5H), 7.35-7.25 (m, 3H), 6.73 (m, 1H), 4.82 (t, 1H), 4.65 (dd, 1H),3.83 (m, 1H), 3.34-2.92 (m, 61), 2.74 (m, 1H), 2.68 (s, 3H), 2.35-2.28(m, 3H), 2.02-1.67 (m, 8H), 1.00 (d, 3H). MS APCI, m/z=688 (M⁺).Analysis for C₃₈H₃₉N₃O₃SCl₂.1.0C₆H₈O₇.2.0H₂O. Calculated: C, 57.64; H,5.60; N, 4.58. Found: C, 57.39; H, 5.43; N, 4.46.

[0131] The requisite 3i was prepared as follows.

[0132] 3e

[0133] A mixture of 1d (1.28 g, 2.36 mmol), DMF (20 mL), Cs₂CO₃ (0.962g, 2.95 mmol) was stirred for 35 min at RT,R-(−)-3-bromo-2-methyl-1-propanol (0.28 mL, 2.60 mmol) added and themixture heated at 104° C. for 2 h. After cooling to RT a second portionof R-(−)-3-bromo-2-methyl-1-propanol (0.28 mL, 2.60 mmol) was added andthe mixture heated overnight at 104° C. The reaction mixture wasquenched with NH₄Cl and worked up as described for 1e. The crude productwas purified by gradient chromatography (eluting with 5%, 10%, 30%, 50%Et₂O/DCM) to yield 3e (0.822 g, 57%) as a light yellow solid. ¹H NMR(300 MHz, CDCl₃) δ 8.22 (s, 1H), 7.85 (m, 1H), 7.59 (m, 1H), 7.48 (m,1H), 7.37 (m, 2H), 7.18 (dd, 1H), 6.21 (t, 1H), 4.27-4.17 (m, 2H),4.0-3.64 (m, 5H), 3.47 (m, 1H), 3.19 (m, 1H), 2.72 (m, 1H), 2.17-2.0 (m,2H), 1.84 (m, 1H), 1.16 (d, 3H), 0.88 (s, 9H), 0.014 (s, 6H). MS APCI,m/z=615 (M⁺).

[0134] 3f

[0135] Using the conditions described in the preparation of 1f, 3e (1.39g, 2.264 mmol) was reacted with methanesulfonyl chloride (0.20 mL, 2.54mmol). The crude product was purified by gradient chromatography (40%,20% hexane/Et₂O) to yield 3f (1.41 g, 90%) as a white solid. ¹H NMR (300MHz, CDCl₃) δ 8.22 (s, 1H), 7.85 (m, 1H), 7.63-7.54 (m, 2H), 7.49-7.36(m, 3H), 7.18 (dd, 1H), 6.14 (t, 1H), 4.46-4.34 (m, 2H), 4.25-4.14 (m,2H), 3.93-3.88 (m, 2H), 3.67 (m, 1H), 3.48 (m, 1H), 3.18 (m, 1H), 3.11(s, 3H), 2.44 (m, 1H), 2.03 (m, 1H), 1.85 (m, 1H), 1.20 (d, 3H), 0.87(s, 9H), 0.13 (s, 6H). MS APCI, m/z=693 (M⁺).

[0136] 3g

[0137] To a stirred solution of 3f (1.41 g, 2.04 mmol) in THF (30.0 mL)was added 60% NaH (0.082 g, 2.04 mmol) and the mixture refluxed for 6 hand allowed to stir and cool in the bath to RT overnight. The reactionwas worked up as described in the preparation of 1g. Purification bygradient chromatography (80%, 70% hexane/Et₂O) gave 3g (0.498 g, 38%) asa white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.13 (s, 1H), 7.71 (m, 1H),7.50-7.36 (m, 4H), 7.26 (m, 1H), 6.65 (m, 1H), 4.83 (t, 1H), 4.65 (m,1H), 3.82 (m, 1H), 3.61 (m, 1H), 3.40 (m, 1H), 3.31-3.10 (m, 4H), 2.36(m, 1H), 1.98-1.84 (m, 2H), 0.98 (d, 3H), 0.89 (s, 9H), 0.015 (s, 6H).MS APCI, m/z=597 (M⁺).

[0138] 3h

[0139] Using the desilylation conditions described in the preparation of1h, 3g (0.493 g, 0.826 mmol) was reacted with 5% HF/CH₃CN (8.25 mLHF/74.33 mL CH₃CN). Purification by gradient chromatography (0.5%, 1.0%MeOH/DCM) gave 3h (0.345 g, 87%) as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 8.13 (s, 1H), 7.72 (m, 1H), 7.48-7.36 (m, 4H), 7.25 (m, 1H),6.67 (m, 1H), 4.83 (t, 1H), 4.63 (m, 1H), 3.82 (m, 1H), 3.68 (m, 1H),3.44 (m, 1H), 3.32-3.11 (m, 4H), 2.34 (m, 1H), 2.07-1.86 (m, 2H), 1.51(m, 1H), 0.98 (d, 3H). MS APCI, m/z=483 (M⁺). Analysis forC₂₆H₂₄N₂O₃Cl₂.0.5H₂O. Calculated: C, 63.42; H, 5.11; N, 5.68. Found: C,63.37; H, 4.95; N, 5.65.

[0140] 3i

[0141] Compound 3h (0.24 g, 0.497 mmol) was reacted with oxalylchloride/DMSO under the standard Swern oxidizing conditions described inthe preparation of 1i. Following gradient chromatography (1%, 20%, 50%Et₂O/DCM) 3i (0.20 g, 84%) was obtained as a white solid. ¹H NMR (300MHz, CDCl₃) δ 9.79 (s, 1H), 8.15 (s, 1H), 7.73 (m, 1H), 7.52-7.37 (m,4H), 7.25 (m, 1H), 6.69 (m, 1H), 4.78 (t, 1H), 4.63 (dd, 1H), 3.83 (m,1H), 3.65 (m, 1H), 3.27 (m, 2H), 3.17 (m, 1H), 2.90 (d, 2H), 2.34 (m,1H), 1.02 (d, 3H). MS APCI, m/z=481 (M⁺).

Example 4

[0142]

[0143] Compound 3i (0.234 g, 0.486 mmol) was reacted with 2Mdimethylamine in THF (0.29 mL, 0.583 mmol) in the presence of sodiumcyanoborohydride under the reductive amination conditions described inthe preparation of 1. The crude product was purified by gradientchromatography (eluting with 2%, 5%, 10% MeOH/DCM) to give 4 (0.214 g,86%) as a white solid which was converted to the citrate salt. ¹H NMR(300 MHz, CDCl₃) δ 8.13 (s, 1H), 7.71 (m, 1H), 7.53-7.35 (m, 4H), 7.26(In, 1H), 6.67 (m, 1H), 4.83 (t, 1H), 4.64 (dd, 1H), 3.82 (m, 1H),3.27-3.05 (m, 4H), 2.35-2.08 (m, 9H), 1.93-1.77 (m, 2H), 0.98 (d, 3H).MS APCI, m/z=510 (M⁺). Analysis for C₂₈H₂₉N₃O₂Cl₂.1.0C₆H₈O₇.1.5H₂O.Calculated: C, 55.97; H, 5.52; N, 5.75. Found: C, 56.08; H, 5.26; N,5.55.

Example 5

[0144]

[0145] 5f

[0146] A stirred mixture of 1d (2.505 g, 4.62 mmol), DMF (34 mL), K₂CO₃(0.958 g, 6.93 mmol), and epichlorohydrin (0.41 mL, 5.197 mmol) washeated in a 100° C. oil bath. Over the course of 6 days of heating thefollowing were added: epichlorohydrin (1.13 equiv./day, 6.8 equiv.total) and K₂CO₃ (1.5 equiv.). The reaction mixture was partitionedbetween DCM and a large volume of water. The organic was collected,washed twice with large volumes of water, dried (Na₂SO₄) and the solventremoved in vacuo. Purification of crude product by gradientchromatography (eluting with 2.5%, 5.0% Et₂O/DCM) yielded 5e (0.337 g,12%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.21 (s, 1H), 7.85 (m,1H), 7.62-7.54 (m, 3H), 7.45-7.40 (m, 2H), 7.19 (d, 1H), 6.28 (m, 1H),4.50 (m, 1H), 4.07 (m, 1H), 3.87-3.81 (m, 2H), 3.65 (m, 1H), 3.49-3.39(m, 2H), 3.17 (m, 1H), 2.90 (m, 1H), 2.72 (m, 1H), 2.02 (m, 1H), 1.84(m, 1H), 0.85 (s, 9H), 0.019 (s, 6H), MS APCI, m/z=599 (M⁺) and 5f(0.518 g, 19%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.23 (d, 1H),7.83 (t, 1H), 7.70-7.53 (m, 3H), 7.40 (m, 2H), 7.15 (m, 1H), 4.70 (m,1H), 4.32-3.12 (m, 9H), 2.23 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 0.86(s, 9H), 0.80 (s, 6H). MS APCI, m/z=599 (M⁺).

[0147] A mixture of 5e (0.337 g, 0.564 mmol) DMF (8.0 mL) and K₂CO₃(0.078 g, 0.564 mmol) was stirred in a 100° oil bath for 17 h and workedup and purified as above to yield additional 5f (0.188 g, 56% from 5e,total 5f from 1d=0.706 g, 26%).

[0148] 5h

[0149] Using the desilylation conditions described for 1h, 5f (0.704 g,1.18 mmol) was reacted with 5% HF/CH₃CN (12 mL 50% HF/106 mL CH₃CN).Purification by gradient chromatography (1%, 2%, 5% MeOH/DCM) gave 5h(0.483 g, 85%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.24 (d, 1H),7.85-7.53 (m, 4H), 7.40 (m, 2H), 7.16 (m, 1H), 4.69 (m, 1H), 4.13 (m,1H), 3.87-3.71 (m, 4H), 3.53-3.25 (m, 4H), 2.35 (m, 1H), 2.07-1.73 (m,3H). MS APCI, m/z=485 (M⁺).

Example 6

[0150] A solution of compound 6p (0.78 g), N,N-diisopropylethylamine(0.54 mL) and bis-(2-oxo-3-oxazolidinyl)-phosphinic chloride (0.40 g) inacetonitrile (40 mL) was stirred for 1 h. Additionaldiisopropylethylamine (0.14 mL) andbis-(2-oxo-3-oxazolidinyl)-phosphinic chloride (0.10 g) were added andthe mixture stirred for 0.5 h, concentrated, diluted with EtOAc; washedwith 0.5 N HCl, then brine; dried over MgSO₄, filtered, concentrated,and purified by flash chromatography using 20-30% EtOAc/hexanes toafford 0.41 g of desired product as a foam solid. ¹H NMR (300 MHz,CDCl₃) δ 8.29 (s), 8.23 (s), 8.04 (d), 7.91 (d), 7.80 (m), 7.66 (t),7.50 (m), 7.37 (m), 7.28 (m), 7.13 (dd), 6.69 (d), 5.67 (m), 5.11-4.74(m), 4.62 (m), 4.02-3.68 (m), 3.49-2.98 (m), 2.64-2.43 (m); MS APCI,m/z=465 (M⁺).

[0151] Compound 6p was prepared as follows.

[0152] 6b

[0153] A mixture of NaOH (2.12 g) in methanol (100 mL) was stirred untilthe solution was homogeneous. Sodium iodide (3.98 g) and compound 6a(5.00 g) were added and stirring continued for 30 min. The resultingsuspension was cooled to 0° C. and a 5.25% (w/v) aqueous solution ofsodium hypochlorite was added dropwise and stirring continued for 1 h.Saturated sodium thiosulfate (25 mL) was added and after 5 min thesolution was acidified to pH 2 by addition of 6 N HCl resulting in theformation of a yellow precipitate which was filtered and washed withwater (50 mL). The precipitate was transferred to a round-bottomedflask, dissolved in methanol (70 mL) and toluene (100 mL), concentrated,redissolved in methanol (70 mL), concentrated, redissolved again inmethanol (70 mL) and toluene (100 mL) and concentrated to afford theproduct as a yellow solid (6.26 g). MS m/z 313 (M−1). ¹H NMR (DMSO-d₆):δ 12.41 (broad, 1H), 8.63 (s, 1H), 8.05-7.97 (m, 2H), 7.70 (m, 1H), 7.42(m, 1H).

[0154] 6c

[0155] A solution of compound 6b (8.0 g), dimethyl sulfate (8.03 g),powdered potassium carbonate (8.80 g), and dry acetone (150 mL) washeated under reflux for 18 h. The solution was cooled to roomtemperature, triethylamine (15 mL) was added, and stirring continued for30 min. The solution was filtered through a pad of Celite and washedwith dry acetone (50 mL). The filtrate was concentrated to a yellow oil,diluted with EtOAc, and washed successively with 1N HCl (100 mL),saturated aqueous sodium bicarbonate (100 mL), and brine (100 mL). Theorganic phase was dried (sodium sulfate), filtered, concentrated, andpurified by chromatography (0-10% EtOAc in hexanes) to afford theproduct as a yellow oil (5.53 g). ¹H NMR (DMSO-d₆) δ 8.47 (s, 1H), 8.09(m, 2H), 7.74 (m, 1H), 7.61 (m, 1H), 3.94 (s, 3H), 3.87 (s, 3H).

[0156] 6d

[0157] Based on the procedure of Wood, J L; Khatri, N A; Weinreb, S M;Tetrahedron Lett; 51, 4907 (1979), compound 6c (5.0 g) was suspended inxylenes (100 mL), cooled to 0° C., dimethylaluminum amide solution(approximately 37 mmol) was added and the solution heated under refluxfor 2.5 h. The solution was then cooled to 0° C., acidified to pH 2 byaddition of 1N HCl, and extracted with EtOAc (3×100 mL). The combinedEtOAc extracts were washed with saturated aqueous sodium bicarbonate(150 mL) and brine (150 mL), dried (sodium sulfate), filtered,concentrated, and purified by chromatography (1:1 EtOAc:DCM, then 10-20%EtOAc in DCM) to afford the product as a white solid (3.29 g). ¹H NMR(DMSO-d₆): δ 8.69 (s, 1H), 8.24-8.04 (m, 2H), 7.91-7.81 (m, 1H),7.76-7.65 (m, 1H), 3.99 (s, 3H); MS m/z 311 (M+1).

[0158] 6e

[0159] Through a suspension of compound 6d (0.250 g), Pd(OAc)₂ (0.018g), triethylamine (0.081 g) and methanol (20 mL) was bubbled carbonmonoxide for 25 min, then stirred at 70° C. under carbon monoxide (1atm) for 18 h. The cooled solution was filtered, rinsed with methanol(20 mL) and DCM (20 mL), concentrated, preadsorbed onto silica (1 g) andpurified by chromatography (0-10% EtOAc in hexanes) to afford theproduct as a white solid (0.113 g). ¹H NMR (DMSO-d₆): δ 8.78 (s, 1H),8.12-8.09 (m, 1H), 7.84-7.78 (m, 2H), 7.70-7.63 (m, 1H), 4.02-4.01 (m,6H); IR (cm⁻¹): 2228, 1724, 1296, 1236, 1208, 1017.

[0160] 6f

[0161] A flame dried 250 mL 3-neck flask was charged with magnesiummetal (2.42 g, 99.5 mmol). After cooling to room temperature, diethylether (80 mL), benzene (30 mL) and iodine (12.62 g, 49.7 mmol) wereadded. The reaction mixture was heated under reflux for 2 h and theiodine color dissipated. After cooling to room temperature, thissolution was transferred to compound 6e (10 g, 41.4 mmol) in benzene (30mL) via syringe. The flask was washed with benzene (15 mL) and a yellowprecipitate formed during the addition. The reaction mixture was heatedunder reflux for another 1 h. 1N HCl and EtOAc were added and theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with saturated Na₂S₂O₄, NaCl, water, dried over MgSO₄, filteredand concentrated. The crude product was purified by chromatography (DCM)to afford the product (6.88 g, 73% yield) as a yellow solid. ¹H NMR(CDCl₃) δ 12.82 (s, 1H), 8.81-8.78 (d, 1H), 8.32 (s, 1H), 7.83-7.82 (d,1H), 7.70 (t, 1H), 7.50 (t, 1H), 4.16 (s, 3H). MS (APCI, negative ionmode) m/z 225.92 (M−).

[0162] 6g

[0163] To a solution of compound 6f (6.24 g, 27.5 mmol) in DCM (140 mL)was added triethylamine (4.21 mL, 30.2 mmol) followed bytrifluoromethanesulfonic anhydride (5.05 mL, 30.2 mmol) at 0° C. Themixture was stirred at room temperature for 30 min. Saturated NaHCO₃ wasadded and the aqueous layer was extracted with DCM. The combined organicextracts were dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by chromatography (eluting with DCM) to give theproduct (9.6 g, 97% yield) as a yellow oil. ¹H NMR (CDCl₃) δ 8.44 (s,1H), 8.29-8.04 (d, 1H), 7.01-7.98 (d, 1H), 7.84 (m, 2H), 4.10 (s, 3H).

[0164] 6h

[0165] A stirred solution of compound 6g (0.28 g, 0.779 mmol), K₃PO₄(0.33 g, 1.55 mmol), methylboronic acid (0.096 g, 1.55 mmol) and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) CH₂Cl₂ (64mg, 0.078 mmol) in THF (8 mL) was heated at 66° C. for 4.5 h. Saturatedaqueous NaHCO₃ was added and the mixture was extracted with EtOAc (3×).The combined organic layers were dried over MgSO₄, filter andconcentrated. The crude product was purified by chromatography (elutingwith 5%, 8% EtOAc/hexane) to give the product (0.139 g, 78% yield) as awhite solid. ¹H NMR (CDCl₃) δ 8.28 (s, 1H), 7.88 (d, 1H), 7.77 (d, 1H),7.67 (t, 1H), 7.55 (t, 1H), 4.08 (s, 3H), 2.66 (s, 3H). MS m/z 226 (M+).

[0166] 6i.

[0167] A solution of compound 6h (4.8 g), N-bromosuccinimide (15.2 g),and 2,2′-azobis(2-methylpropionitrile) (0.35 g) in carbon tetrachloride(85 mL) was heated under reflux for 3 h. The cooled mixture was dilutedwith DCM and water and the excess NBS quenched by adding sodiumthiosulfate pentahydrate (15.2 g) and stirring for 0.5 h. The layerswere separated and the organic washed with water, then brine; dried overMgSO₄; filtered; and concentrated under reduced pressure. The crudematerial was then passed through a plug of silica using 40-60%DCM/hexanes as eluant to afford the desired compound as a white solid(5.2 g). ¹H NMR (300 MHz, CDCl₃) δ 8.33 (s, 1H), 7.90 (m, 2H), 7.69 (m,2H), 4.82 (s, 2H), 4.13 (s, 3H); MS APCI, m/z=304 (M⁺).

[0168] 6k

[0169] A solution of compound 6j (Shenvi, A; Jacobs, R T; Miller, S C;Ohnmacht, C J, Jr.; Veale, C A. EP 680962) (2.0 g), diisopropylethylamine (1.56 mL), ethanolamine (0.59 mL), and 4-dimethylaminopyridine(1.0 g) in DCM (32 mL) was cooled to 5° C. and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.65 g) wasadded. The cooling bath was removed and reaction stirred for 50 min,then heated briefly under reflux. After cooling, additional ethanolamine(0.3 mL) was added and stirring continued for 10 min. The mixture wasconcentrated, diluted with EtOAc; washed with 1 N HCl, then saturatedaqueous sodium carbonate, then brine; dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography using 30-80% EtOAc/hexanes to afford the desired product(1.0 g) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 7.40 (m, 2H), 7.18 (m, 1H),5.93 (bs, 1H), 5.68 (m, 1H), 5.05 (m, 2H), 3.64 (m, 2H), 3.40 (m, 3H),2.84 (m, 1H), 2.48 (m, 1H); MS APCI, m/z=288 (M⁺).

[0170] 6l

[0171] To a solution of compound 6k (1.5 g) in Et₂O (105 mL) was added13 mL of a 1M solution of lithium aluminum hydride in THF. The mixturewas heated under reflux for 3 h. After cooling, 10 mL of saturatedaqueous sodium sulfate was cautiously added and the suspension stirredfor 0.5 h. Solid sodium sulfate (10 g) was added and the suspensionstirred for 0.5 h, filtered through celite, rinsed with EtOAc,concentrated under reduced pressure, and purified by passing through aplug of silica with 3-7% methanol/DCM to afford the desired material(1.25 g) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 7.39 (d, 1H), 7.26 (d,1H), 7.03 (dd, 1H), 5.64 (m, 1H), 4.98 (m, 2H), 3.55 (t, 2H), 2.71-2.94(m, 5H), 2.26-2.51 (m, 2H); MS APCI, m/z=274 (M⁺).

[0172] 6m

[0173] To a solution of compound 6l (1.25 g) in dioxane (10 mL), water(10 mL) and sodium carbonate (0.51 g) was cooled to 0° C. anddi-t-butyldicarbonate (1.04 g) was slowly added as a solution in dioxane(5 mL). After 1 h the mixture was diluted with EtOAc, washed with water,then brine; dried over MgSO₄; filtered and concentrated under reducedpressure. The resulting residue was passed through a plug of silica toafford 1.4 g of desired product as an oil. ¹H NMR (300 MHz, CDCl₃) δ7.37 (d, 1H), 7.26 (d, 1H), 7.00 (m, 1H), 5.62 (m, 1H), 5.00 (m, 2H),3.71-2.94 (m, 7H), 2.34 (m, 2H), 1.41 (s, 9H).

[0174] 6o

[0175] A mixture of compound 6m (1.4 g), compound 6i (1.36 g), andsodium hydride (0.18 g of 60% dispersion in mineral oil) in DMF (6 mL)and THF (6 mL) was stirred overnight. Additional sodium hydride (30 mgof 60% dispersion in mineral oil) was added and the reaction heated at50° C. for 0.25 h, then at 60° C. for another 0.25 h. The mixture wascooled, diluted with EtOAc, washed with water (twice), then brine; driedover MgSO₄, filtered, concentrated under reduced pressure to affordcompound 6n which was used without purification. A solution of compound6n and TFA (10 mL) was stirred in DCM (10 mL), heated under reflux for20 min, concentrated, diluted with DCM, concentrated again, thenpurified by flash chromatography using 1-5% methanol/DCM to affordcompound 6o (1.5 g) foam solid. ¹H NMR (300 MHz, CDCl₃) δ 8.34 (s, 1H),7.95 (d, 1H), 7.76 (m, 3H), 7.31 (d, 1H), 7.24 (d, 1H), 7.05 (dd, 1H),5.55 (m, 1H), 4.98 (m, 2H), 4.76 (d, 2H), 4.03 (s, 3H), 3.83 (t, 2H),3.42-3.12 (m, 5H), 2.38 (m, 2H); MS APCI, m/z=497 (M⁺).

[0176] 6p

[0177] A mixture of compound 6o (1.5 g) and pyridine hydrochloride (3.5g) was heated with stirring in an pre-heated oil bath for 15 min at 180°C. The cooled residue was partitioned with EtOAC and water, washed with0.5 N HCl, the brine, dried over MgSO₄, filtered, concentrated underreduced pressure, then diluted with Et₂O to afford a precipitate whichwas isolated to afford the product (1.1 g) as a tan solid. ¹H NMR (300MHz, CDCl₃) δ 9.11 (bs, 1H), 8.17 (s, 1H), 7.98 (d, 1H), 7.82 (d, 1H),7.73 (t, 1H), 7.62 (t, 1H), 7.40 (d, 1H), 7.27 (d, 1H), 7.11 (dd, 1H),5.61 (m, 1H), 5.05 (m, 2H), 4.97 (s, 2H), 4.03 (m, 2H), 3.40 (m, 2H),3.20 (m, 3H), 2.48 (m, 2H); MS APCI, m/z=483 (M⁺).

Example 7

[0178] A stream of ozone was passed through a solution of the materialof Example 6 (0.40 g) in methanol (10 mL) and DCM (20 mL) at −78° C. for5 min and the blue solution color persisted. Stirring was continued for10 min then nitrogen was bubbled through for 5 min. The reaction warmedto −30° C. then dimethyl sulfide (0.32 mL) was added. The mixture waswarmed to room temperature and stirred 1.5 h, concentrated, and purifiedby flash chromatography using 50-60% EtOAc/hexanes to afford the product(0.30 g) as a foam solid. ¹H NMR (300 MHz, CDCl₃) δ 9.79 (d), 8.31 (s),8.23 (s), 8.03 (d), 7.92 (d), 7.80 (m), 7.67 (t), 7.59-7.37 (m), 7.28(m), 7.19 (dd), 6.66 (d), 5.08-4.74 (m), 4.61 (m), 4.05-3.01 (m), 2.96(d), 2.76 (m); MS APCI, m/z=467 (M⁺).

Example 8

[0179] A solution of the material of Example 7 (0.10 g), triethylamine(0.034 mL), and dimethylamine hydrochloride (23 mg) was dissolved in 2mL of methanol. Acetic acid was added dropwise until the pH was between4 and 5. After stirring for 1.5 h sodium cyanoborohydride (23 mg) wasadded as a solution in 1 mL of methanol in three portions over 10 minand the reaction was allowed to stir for 3 h. It was then concentrated;diluted with EtOAc; washed with water, then brine; dried over MgSO₄;filtered; concentrated; then purified by flash chromatography using6-10% methanol/DCM. Residual triethylamine was removed by dissolving inEtOAc, washing with water, then brine; drying over MgSO₄, filtering andconcentrating under reduced pressure to afford the product (80 mg) as anoil. This material was converted to the citrate salt by combining withan equimolar amount of citric acid in methanol, then drying. ¹H NMR (300MHz, DMSO-d₆) δ 8.68 (s), 8.62 (s), 8.09 (d), 8.01 (d), 7.90 (d),7.82-7.59 (m), 7.40 (m), 6.44 (d), 4.87 (m), 4.71 (t), 4.32 (dd), 3.99(t), 3.89-3.64 (m), 3.42-2.94 (m), 2.83-2.55 (m), 2.10; MS APCI, m/z=496(M⁺).

Example 9

[0180] A solution of the material of Example 7 (50 mg),4-[(S)-2-methylsulfinylphenyl]-piperidine (Shenvi, A B; Jacobs, R T;Miller, S C; Ohnmacht, C J, Jr.; Veale, C A., WO 9516682) (30 mg), andacetic acid (0.012 mL) was stirred in methanol (2 mL) for 0.5 h. Sodiumcyanoborohydride (12 mg) was added as a solution in methanol (1 mL) inthree portions over 10 min., stirred 2 h, then concentrated underreduced pressure. The residue was diluted with EtOAc; washed with water,then brine; dried over MgSO₄, filtered, concentrated, and purified byflash chromatography to afford the product (50 mg) as a solid, thenconverted to the citrate salt according to the procedure described forExample 8. ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (s), 8.62 (s), 8.09 (d),8.01 (d), 7.94-7.36 (m), 6.47 (d), 4.87 (m), 4.72 (t), 4.00 (t),3.90-3.64 (m), 3.51-1.75 (m); MS APCI, m/z=674 (M⁺).

Example 10

[0181] A solution of the material of Example 7 (50 mg) and sodiumborohydride (5 mg) in methanol (2 mL) was stirred for 0.5 h,concentrated, diluted with EtOAc, washed with water, then brine, driedover MgSO₄, filtered, concentrated, and purified by flash chromatographyusing 60-100% EtOAc/hexanes to afford the product (40 mg) as a solid. ¹HNMR (300 MHz, CDCl₃) δ 8.31 (s), 8.23 (s), 8.08 (d), 7.92 (d), 7.80 (m),7.67 (t), 7.58-7.26 (m), 7.15 (dd), 6.68 (d), 5.09-4.63 (m), 4.02-3.01(m), 2.62 (m), 1.96 (m); MS APCI, m/z=469 (M⁺).

Synthesis of Examples 11-14

[0182] TABLE 2

Ex. MS^(a) HPLC^(b) Salt^(c) 11 510.4 2.41 A 12 510 2.14 B 13 510.3 2.50A 14 510.3 2.45 A R²⁷ is:

[0183] Compound 11 was prepared according to the procedure described forCompound 8 except (S)-(−)-2-amino-1-propanol was used in place ofethanolamine for the intermediate corresponding to 6k and the aminoalcohol was reacted with the acid chloride adduct (prepared from thecarboxylic acid using oxalyl chloride) of 6j under Schotten-Baumannconditions. Similarly, compounds 12, 13, and 14 were prepared by using(respectively) (R)-1-amino-2-propanol, (S)-1-amino-2-propanol, or(R)-(−)-2-amino-1-propanol in place of aminoethanol. TABLE 3

Example R²⁸ Amine MS^(a) HPLC^(b) Salt^(c) 15

538 2.26 B 16

540 2.1 B 17

512 2.24 B 18

526 2.46 A 19

573 2.39 A 20

576 2.33 A 21

593 2.35 A 22

600 2.9 A 23

602 2.85 A 24

567 2.33 A 25

522 2.6 A 26

553 2.44 A 27

651 2.6 A 28

646 2.8 A 29

607 2.56 A 30

538 2.68 A 31

567 2.33 A 32

590 2.33 A 33

552 2.55 A 34

566 2.64 A 35

616 2.79 A 36

536 2.61 A 37

564 2.49 A 38

540 2.42 A 39

553 2.27 A 40

554 2.54 A 41

522 2.49 A 42

556 2.55 A 43

540 2.38 A 44

587 2.33 A 45

602 2.57 A 46

616 2.68 A 47

579 2.17 A 47

651 2.66 A 49

683 2.48 A 50

647 2.35 A 51

496 2.27 A 52

642 2.53 A 53

536 2.44 A 54

550 2.42 A 55

565 2.13 A 56

626 2.71 A 57

525 2.09 A

Synthesis of Examples 15-57

[0184] Compounds 15-57 were prepared according to the proceduredescribed for Compound 12 except the aldehyde was reacted with the amineindicated in Table 3 in place of dimethyl amine. Each compound waspurified by reverse phase HPLC.

Example 58

[0185] Compound 58a was prepared according to the procedure describedfor Compound 6 except (R)-1-amino-2-propanol was used in place ofethanolamine for the intermediate corresponding to 6k and the aminoalcohol was reacted with the acid chloride adduct (prepared from thecarboxylic acid using oxalyl choride) of 6j under Schotten-Baumannconditions. Compound 58a was oxidized to aldehyde 58b using osmiumtetroxide/sodium peroidate, then oxidized to the carboxylic acid 58using Jones reagent. HPLC: 2.62 min, MS, m/e=497.4 (see Table 2 legendfor details). TABLE 4

59-70 Example R³⁰ Amine MS^(a) HPLC^(b) 59

† 496.2 2.29 60

524.3 2.53 61

539.3 2.04 62

581.4 2.25 63

587.3 2.11 64

510.4 2.51 65

567.47 2.22 66

579.47 2.29 67

601.47 2.24 68

604.49 2.21 69

567.49 2.29 70

536.45 2.61

[0186] Synthesis of Compounds 59-70. Compounds 59-70 were prepared byreaction of the corresponding acid chloride derived from 58 with theamines indicated in Table 4 in DCM, then purified by reverse phase HPLC.The requisite acid chloride was prepared from 58 with oxalyl chloride inDCM using standard conditions, dried under vacuum, and used withoutpurification. TABLE 5

Example R³¹ MS^(a) HPLC^(b) Synthesis 71 HO— 483.4 2.82 Reduction of 58using NaBH₄ 72 Cl 501.4 3.35 Chlorination of 71 using hexa-chloroacetone and PPh₃ 73 Br 545.3 3.4 Bromination of 71 using Ph₃PBr₂

[0187]

Example 74

[0188] Example 74 was prepared according to the method described for 58aexcept 2-bromomethyl-1-naphthoic acid methyl ester was used in place of6i, and the methyl ester was hydrolyzed to the carboxylic acid (toafford the compound corresponding to 6p) using LiOH (3.1 equivalents) inwater/ethylene glycol at 150° C. overnight instead of using pyridinehydrochloride. HPLC: 3.33 min, MS; m/e=454.42 (see Table 2 legend fordetails). TABLE 6

Example R³² Amine MS^(a) HPLC^(b) Salt^(c) 75

485.45 2.51 A 76

513.46 2.61 A 77

487.41 2.53 A

[0189] Synthesis of Compounds 75-77. Compounds 75-77 were prepared byreductive amination of the aldehyde(S)-3-(3,4-dichlorophenyl)-4-((R)-9-methyl-12-oxo-7,9,10,12-tetrahydro-8-oxa-11-aza-cycloocta[α]naphthalen-11-yl)-butyraldehydewith the amines indicated in Table 6 in methanol with sodiumcyanoborohydride under conditions similar to those described for thepreparation of compound 8, followed by purification by reverse phaseHPLC. The requisite aldehyde was prepared by oxidation of 74 usingosmium tetroxide/sodium peroidate.

[0190] Sulfur Compounds

[0191] Intermediate S1: Methyl3-Cyano-2-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthoate

[0192] To a solution of methyl 3-cyano-2-hydroxy-1-napthoate (3.1 g,13.6 mmol) in dry methylene chloride (60 mL) at 0° C. was addedtriethylamine (2.14 mL, 15.4 mmol) followed by dropwise addition oftrifluoromethylsulfonic anhydride. After stirring for an additional 30min at 0° C. and 30 min at ambient temperature, the reaction mixture wasdiluted with methylene chloride (60 mL), washed with 0.5 N HCl (2×40 mL)and saturated NaHCO₃ (2×40 mL), dried (MgSO₄), filtered, and evaporatedto dryness. The residue was purified by chromatography on silica gel inmethylene chloride to give 3.7 g (75% yield) of the title compound.

[0193] Intermediate S2: Methyl2-({2-[(tert-Butoxycarbonyl)amino]ethyl}thio)-3-cyano-1-naphthoate

[0194] To a suspension (vacuum degassed 3 times) of potassium carbonate(110 mg, 0.78 mmol) in toluene (5 mL) under nitrogen was addedtert-butyl 2-mercaptoethylcarbamate (131 μL, 0.78 mmol) followed bystirring at ambient temperature for 1 h. To this suspension was added bycannula a solution (vacuum degassed 3 times) of methyl3-cyano-2-{[(trifluoromethyl)-sulfonyl]oxy}-1-naphthoate (Intermediate1, 200 mg, 0.56 mmol), (R)-Tol-BINAP (44.1 mg, 0.07 mmol), andpalladium(II) acetate (14 mg, 0.06 mmol) in toluene (10 mL). Theresulting suspension was stirred at 80° C. for 20 h, cooled,(reducedvolume by ½ under reduced pressure, diluted with ether (12 ml) andmethylene chloride (6 ml), washed organic layer with 20% K₂CO₃ (2×15ml), water and brine, dried over Na₂SO₄, filtered, and evaporated todryness. The residue was precipitated from 10% ethyl acetate in hexanesto give 150 mg of the title compound. An additional 40 mg (88% overallyield) of the title compound was isolated from the mother liquor bychromatography on silica gel in 20% ethyl acetate/hexanes.

[0195] Intermediate S3: Methyl2-[(2-Aminoethyl)thio]-3-cyano-1-naphthoate Hydrochloride

[0196] To a solution of methyl2-({2-[(tert-butoxycarbonyl)amino]ethyl}thio)-3-cyano-1-naphthoate(Intermediate 2, 140 mg, 0.36 mmol) in ethyl acetate (20 mL) cooled to−20° C. was bubbled HCl gas for 5 min. The reaction mixture was allowedto warm to ambient temperature over 2 h and then evaporated to drynessto gave the title compound as an off white solid (115 mg) which was usedwithout further purification.

[0197] Intermediate S4: (2S)-2-(3,4-Dichlorophenyl)pent-4-enal

[0198] To a solution of oxalyl chloride (0.713 mL, 8.24 mmol) at −78° C.in dry methylene chloride (100 mL) under nitrogen in a three neckedflask was added dropwise a solution of DMSO (1.37 mL, 19.8 mmol) inmethylene chloride (4 mL) with stirring at −78° C. for an additional 20min. A solution of (2S)-2-(3,4-dichlorophenyl)pent-4-en-1-ol (1.26 g,5.45 mmol) in methylene chloride (50 mL) was added dropwise (45 min)while maintaining the reaction temperature below −60° C. After stirringat −60° C. for an additional 2 h, triethylamine (4.6 mL, 33.3 mmol) wasadded dropwise. The stirred reaction mixture was allowed to warm toambient temperature for 2 h, cooled in ice, quenched by addition ofwater (80 mL), and stirred for an additional 30 min. The organic layerwas washed with water and brine, dried (Na₂SO₄), and evaporated to give1.25 g of the title compound which was used without furtherpurification. This material was determined to be about 72% pure by HPLC.

[0199] Intermediate S5: Methyl3-Cyano-2-[(2-{[(2S)-2-(3,4-dichlorophenyl)pent-4-enyl]amino}ethyl)thio]-1-naphthoateHydrochloride

[0200] To a solution of methyl2-[(2-aminoethyl)thio]-3-cyano-1-naphthoate hydrochloride (Intermediate3, 530 mg, 1.65 mmol) in methanol (100 mL) was added triethylamine (250μL, 1.82 mmol). After 30 min (2S)-2-(3,4-dichlorophenyl)pent-4-enal{Intermediate 4, 525 mg (72% pure), 1.65 mmol} and the pH was adjustedto 4-5 with acetic acid. After 30 min a solution of sodiumcyanoborohydride (200 mg, 3.20 mmol) in methanol (2 mL) was added andreaction mixture stirred at ambient temperature overnight. Reactionmixture volume reduced by half and 20% K₂CO₃ (50 mL) was added. Reactionmixture volume reduced further to about 50 mL and methylene chloride(100 mL) was added. The organic layer was washed with brine, dried(Na₂SO₄), and evaporated to an oil which was chromatography on silicagel in 5% MeOH/CHCl₃ to give 730 mg of the free base. The free base wasdissolved in HCl/MeOH and evaporated to dryness to give 780 mg of thetitle compound.

[0201] Intermediate S6:3-Cyano-2-[(2-{[(2S)-2-(3,4-Dichlorophenyl)pent-4-enyl]amino}ethyl)thio]-1-naphthoic Acid

[0202] An evenly distributed mixture of methyl3-cyano-2-[(2-{[(2S)-2-(3,4-dichlorophenyl)pent-4-enyl]amino}ethyl)thio]-1-naphthoatehydrochloride (Intermediate 5, 150 mg, 0.28 mmol) and pyridinehydrochloride (487 mg, 4.20 mmol) was heated at 180° C. for 5 min,cooled, and partitioned between ethyl acetate and water. The organiclayer was washed with 1 N HCl and brine, dried (Na₂SO₄), and evaporatedto dryness to give 135 mg (100% yield) of the title compound which wasused without further purification.

Example 78

[0203]2-[(2S)-2-(3,4-Dichlorophenyl)pent-4-enyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile

[0204] To a solution of3-cyano-2-[(2-{[(2S)-2-(3,4-Dichlorophenyl)pent-4-enyl]amino}ethyl)thio]-1-naphthoicacid (Intermediate 6, 135 mg, 0.28 mmol) in dry acetonitrile (6 mL)under nitrogen at 0° C. was added diisopropylethyl amine (146 μL, 0.84mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl, 86 mg,0.34 mmol). Stirring was continued for 45 min as the reaction mixturewas allowed to warm to ambient temperature. The reaction mixture wasdiluted with ethyl acetate (50 mL), washed with 0.5 N HCl and brine,dried (Na₂SO₄), and evaporated to a residue which was chromatographed onsilica gel in 25-40% EtOAc/Hexanes to give 85 mg of partially purifiedmaterial. A portion (50 mg) of this material was chromatographed onsilica gel in 20% EtOAc/Hexanes to give 35 mg of the title compound.

[0205] Intermediate 78a:2-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile

[0206] Intermediate 78b:(5S)-2-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile5-oxide

[0207] Intermediate 78c:(5R)-2-[(2S)-2-(3,4-dichlorophenyl)₄-oxobutyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile5-oxide

[0208] * Throughout this document, the use of “R” and “S” when referringto the stereochemistry of sulfoxides in the macrocycle, is meant todesignate the relative stereochemistry of the sulfoxide. The absolutestereochemistries were not assigned.

[0209] To a solution of2-[(2S)-2-(3,4-dichlorophenyl)pent-4-enyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile(Example 1, 225 mg, 0.50 mmol) in 3:1 THF/water (10 mL) under nitrogenat 0° C. was added osmium tetroxide (4% in water, 32.5 μL, 0.01 mmol)followed in 10 min by portion wise addition of sodium periodate over 5min. The reaction mixture was allowed to warm to ambient temperatureover 3 h and clarified by the addition of water. The products wereextracted into ether and organic layer was washed with saturated NaHCO₃and brine, dried (Na₂SO₄), and evaporated to 230 mg of an oil which waschromatographed on silica gel in 10% MeOH/CHCl₃ to give 40 mg ofintermediate 78a, 22 mg of Intermediate 78b and 11 mg of Intermediate78c.

Example 79

[0210]2-[(2S)-2-(3,4-dichlorophenyl)-4-(dimethylamino)butyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile

[0211] To a solution of Intermediate 7a (40 mg, 0.085 mmol) in methanol(2 mL) under nitrogen was added dimethylamine hydrochloride (11 mg, 0.13mmol) and triethylamine (15 μL, 0.11 mmol) followed in 10 min by acidicacid (3 drops to adjust pH to between 4 and 5). After stirring thereaction mixture for 30 min at ambient temperature sodiumcyanoborohydride (9 mg, 0.1445 mmol) in methanol (1 mL) was added withstirring continued for 1 h. The solvent was evaporated and the residuewas dissolved in ethyl acetate (20 mL), washed with water and brine,dried (Na₂SO₄), and evaporated to give 43 mg of crude product which waschromatographed on ammoniated silica gel in 10-15% MeOH/CHCl₃ to give 23mg of the title compound.

Example 80

[0212](5S)-2-[(2S)-2-(3,4-dichlorophenyl)-4-(dimethylamino)butyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile5-oxide

[0213] By the method described in Example 79, Intermediate 78b (19 mg,0.04 mmol) and dimethylamine hydrochloride (5 mg, 0.06 mmol) wereconverted to 15 mg of the title compound.

Example 81

[0214](5R)-2-[(2S)-2-(3,4-dichlorophenyl)-4-(dimethylamino)butyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile5-oxide

[0215] By the method described in Example 79, Intermediate 78c (10 mg,0.021 mmol) and dimethylamine hydrochloride (5 mg, 0.06 mmol) wereconverted to 10 mg of the title compound.

Example 82

[0216]2-[(2S)-2-(3,4-dichlorophenyl)-4-(methoxyamino)butyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile

[0217] By the method described in Example 79, Intermediate 78a (40 mg,0.085 mmol) and methoxyamine hydrochloride (13 mg, 0.154 mmol) wereconverted to 28 mg of the title compound.

Example 83

[0218](5)-2-[(2S)-2-(3,4-dichlorophenyl)-4-(methoxyamino)butyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile5-oxide

[0219] By the method described in Example 79, Intermediate 78b (30 mg,0.06 mmol) and methoxyamine hydrochloride (5 mg, 0.06 mmol) wereconverted to crude product. The crude product was purified on a C-8reverse phase column eluting with a 40-70% CH₃CN/H₂O gradient (0.05%TFA) to give 15 mg of the title compound as its trifluoroacetic acidsalt.

Example 84

[0220]2-[(2S)-2-(3,4-dichlorophenyl)-4-(cyclopropylamino)butyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile

[0221] By the method described in Example 83, Intermediate 78a (70 mg,0.15 mmol) and cyclopropylamine (13 mg, 0.23 mmol) were converted to 45mg of the title compound as its trifluoroacetic acid salt. SulfurCompound LC/MS Parameters Column: HP C-8 5 cm 5 micron 2.1 mm Method I:Fast LC/MS Method 1.4 ml/min 5% B 0-3 min 5-90% B 3 to 4 min hold at 90%B 4-5 min 90-5% B A = 0.05% TFA in H₂0 B = 90:10 CH₃CN:H₂O Method II 15min LC/MS Method 1.4 ml/min 5% B Hold 30 sec 0.5-10 min 5-90% B 10-12min hold at 90% B 12-12.5 min 90-5% B 12.5-14 min hold at 5% B A = 0.05%TFA in H₂O B = 90:10 CH₃CN:H₂O

[0222] Thiazapine Final Product Retention Times Example Method RetentionTime (minutes) M + 1 M + 3 78 II 8.68 467 469 79 I 2.25 498 500 80 I1.98 514 516 81 I 1.96 514 516 82 II 6.64 500 502 83 I 2.12 516 518 84II 6.69 510 512

1. A compound having the formula

wherein: R^(1a) is H, NR⁹R¹⁰, —OR¹⁰, Cl, Br,

R^(1b) and R^(1c) are independently H or —OR⁹, or R^(1b) and R^(1c)together are ═O, ═CH₂ or —OCH₂CH₂O—; R² is H, oxo, —OR⁹ or —CH₃; R³, R⁴,R⁵, R⁶, R⁷ and R⁸ are each independently selected from H, cyano, nitro,trifluoromethoxy, trifluoromethyl, C₁₋₆alkylsulfonyl, halo, —OR⁹,—OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—OC(═O)R⁹, —NR⁹C(═O)R¹⁰, aminosulfonyl and C₁₋₆alkyl substituted by anyof the hereinabove substituents; wherein at least two of R³, R⁴, R⁵, R⁶,R⁷ and R⁸ are H; R⁹ is independently selected from H, C₁₋₆alkyl,C₁₋₄alkoxy, and —OCH₂(CH₂)_(n)phenyl; R¹⁰ is independently H orC₁₋₆alkyl, hydroxyC₁₋₆alkyl, (NR⁹R⁹)C₁₋₆alkyl, (NR⁹R⁹)C(═O)C₁₋₆alkyl,—(CH₂)_(o)R¹⁵; R¹¹ is phenyl, substituted in at least the ortho positionby C₁₋₆alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl,trifluoromethylthio, trifluoromethylsulfinyl, C₁₋₆alkanesulfonamido,C₁₋₆alkanoyl, C₁₋₆alkoxy-carbonyl, succinamido, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl,C₁₋₆alkoxy-C₁₋₆alkylcarbamoyl, N-methylcarbamoyl, C₁₋₆alkanoylamino,ureido, C₁₋₆ureido, di-C₁₋₆alkylureido, amino, C₁₋₆alkylamino, ordi-C₁₋₆alkylamino; R¹² is selected from hydrogen, hydroxy, C₁₋₆alkoxy,C₁₋₆alkanoyloxy, C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino,C₁₋₆alkyl, carbamoyl, C₁₋₆alkylcarbamoyl and bis(C₁₋₆alkyl)carbamoyl;R¹³ is —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—; R¹⁴ is hydrogen,hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy, C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkanoylamino, C₁₋₆alkyl, carbamoyl, C₁₋₆alkylcarbamoyl ordi-C₁₋₆alkylcarbamoyl; R¹⁵ is a 5- or 6-membered saturated orunsaturated heterocycle containing 1 or 2 heteroatoms selected fromnitrogen, oxygen and sulfur and additionally subsituted with 0 or 1 oxogroups; or R¹⁵ is phenyl substituted by 0, 1, or 2 substitutentsselected from halogen, C₁₋₄alkoxy, vicinal-methylenedioxy,—S(═O)_(n)C₁₋₄alkyl, —S(═O)₂NH₂ and C₁₋₄alkyl; M is —C(═O)— or —S(═O)₂—;L is —NH— or —CH₂—; X¹ and X² are independently H or halogen, wherein atleast one of X¹ and X² are halogen; Y and Z are independently selectedfrom CH₂, O, S, S═O and S(═O)₂, wherein at least one of Y and Z is CH₂;n is independently, at each instance, 0 or 1; o is independently, ateach instance, 1, 2 or 3; and any pharmaceutically-acceptable saltthereof.
 2. A compound according to claim 1, wherein: R⁵, R⁶, R⁷ and R⁸are each H.
 3. A compound according to claim 2, wherein: R^(1a) is H,NR⁹R¹⁰, —OR¹⁰, Cl or Br; R^(1b) and R^(1c) are independently H or —OR⁹,or R^(1b) and R^(1c) together are ═O, ═CH₂ or —OCH₂CH₂O—.
 4. A compoundaccording to claim 2, wherein: R^(1a) is Cl or Br; and R^(1b) and R^(1c)are both H.
 5. A compound according to claim 2, wherein: R^(1a) isNR⁹R¹⁰, —OR¹⁰; and R^(1b) and R^(1c) are both H or R^(1b) and R^(1c)together are ═O.
 6. A compound according to claim 1, wherein R^(1a) is HNR⁹R¹⁰, —OR⁹,

R^(1b) and R^(1c) are independently H or —OR⁹, or R^(1b) and R^(1c)together are ═O, ═CH₂ or —OCH₂CH₂O—; R² is H, oxo, —OR⁹ or —CH₃; R³, R⁴,R⁵, R⁶, R⁷ and R⁸ are each independently selected from H, cyano, nitro,trifluoromethoxy, trifluoromethyl, C₁₋₆alkylsulfonyl, halo, —OR⁹,—OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—OC(═O)R⁹, —NR⁹C(═O)R¹⁰, aminosulfonyl and C₁₋₆alkyl substituted by anyof the hereinabove substituents; wherein at least two of R³, R⁴, R⁵, R⁶,R⁷ and R⁸ are H; R⁹ and R¹⁰ are each independently H or C₁₋₆alkyl; R¹¹is phenyl, substituted in at least the ortho position by C₁₋₆alkylthio,C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, trifluoromethylthio,trifluoromethylsulfinyl, C₁₋₆alkanesulfonamido, C₁₋₆alkanoyl,C₁₋₆alkoxy-carbonyl, succinamido, carbamoyl, C₁₋₆alkylcarbamoyl,di-C₁₋₆alkylcarbamoyl, C₁₋₆alkoxy-C₁₋₆alkylcarbamoyl, N-methylcarbamoyl,C₁₋₆alkanoylamino, ureido, C₁₋₆ureido, di-C₁₋₆alkylureido, amino,C₁₋₆alkylamino, or di-C₁₋₆alkylamino; R¹² is selected from hydrogen,hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy, C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkanoyl amino, C₁₋₆alkyl, carbamoyl, C₁₋₆alkylcarbamoyl andbis(C₁₋₆alkyl)carbamoyl; R¹³ is —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—;R¹⁴ is hydrogen, hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy, C₁₋₆alkanoyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino, C₁₋₆alkyl, carbamoyl,C₁₋₆alkylcarbamoyl or di-C₁₋₆alkylcarbamoyl; M is —C(═O)— or —S(═O)₂—; Lis —NH— or —CH₂—; X¹ and X² are independently H or halogen, wherein atleast one of X¹ and X² are halogen; Y and Z are CH₂ or O, wherein Y doesnot equal Z; n is 0 or 1; and any pharmaceutically-acceptable saltthereof.
 7. A compound according to claim 6 wherein R³, R⁴, R⁵, R⁶, R⁷and R⁸ are selected from H, cyano, nitro, —S(═O)C₁₋₆alkyl, halo, —OR⁹,—OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—OC(═O)R⁹, —NR⁹C(═O)R¹⁰, aminosulfonyl and —C₁₋₆alkylcyano; wherein atleast three of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are H;
 8. A compound accordingto claim 6 wherein R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are selected from H, cyano,methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo, nitro,cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl,dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyland acetylamino; wherein at least three of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ areH;
 9. A compound according to claim 6 wherein R³, R⁴, R⁵, R⁶, R⁷ and R⁸are selected from H, cyano, methoxy, ethyl, fluoro and nitro; wherein atleast three of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are H;
 10. A compound accordingto claim 6 wherein: R^(1a) is

R^(1b) is H; and R^(1c) is H.
 11. A compound according to claim 6,wherein: R^(1a) is

R^(1b) is H; and R^(1c) is H.
 12. A compound according to claim 6,wherein R^(1a) is H, NR⁹R¹⁰ or —OR⁹.
 13. A compound according to claim6, wherein R² is —OR⁵ or —CH₃.
 14. A pharmaceutical compositioncomprising a therapeutically-effective amount of a compound according toany one of claims 1 through
 13. 15. A method of treating majordepressive disorder, severe anxiety disorders, stress disorders, majordepressive disorder with anxiety, eating disorders, bipolar disorder,general and specific cravings, substance use disorder, schizophrenicdisorders, psychotic disorders, movement disorders, cognitive disorders,depression and/or anxiety, mania or hypomania, aggressive behaviour,obesity, emesis, rheumatoid arthritis, Alzheimer's disease, cancer,oedema, allergic rhinitis, inflammation, pain,gastrointestinal-hypermotility, Huntington's disease, COPD,hypertension, migraine, bladder hypermotility, or urticaria comprisingadministering a therapeutically-effective amount of an NK1 antagonistaccording to any one of claims 1 through 3.